Low‐Dose Theophylline Reduces Symptoms of Acute Mountain Sickness

Küpper, Thomas; Strohl, Kingman P.; Hoefer, Markus; Gieseler, Ulf; Netzer, Cordula M.; Netzer, Nikolaus C.

doi:10.1111/j.1708-8305.2008.00228.x

Cited by 31 publications

(10 citation statements)

References 39 publications

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“…The negative results of this study are in contrast to a small number of studies unanimously suggesting that methazolamide (Forster, 1982;Wright et al, 1983) and theophylline (Fischer et al, 2000;Küpper et al, 2008) can independently decrease symptoms of AMS, and the more recent suggestion that the combination of the two drugs improves aerobic exercise performance in acute normobaric hypoxia (Scalzo et al, 2015). While each of the aforementioned studies has merit, their study designs were limited in nature and preclude the conclusion that the combination of drugs provides protection from AMS and improves performance at high altitude.…”

Section: Discussioncontrasting

confidence: 99%

“…Theophylline, a methylxanthine, acts as an adenosine receptor antagonist and phosphodiesterase inhibitor and is most commonly prescribed as a bronchodilator for asthmatics. Both theophylline and its ethylenediamine salt, aminophylline, have been shown to reduce AMS symptoms and sleep disturbance at altitude, with few side effects (Fischer et al, 2000(Fischer et al, , 2004Küpper et al, 2008).…”

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confidence: 99%

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Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia

Subudhi

Evero

Reitinger

et al. 2020

Experimental Physiology

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A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry (S pO 2) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (P B = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (= 0.05). The drugs improved resting S pO 2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance. K E Y W O R D S acute mountain sickness, carbonic anhydrase, cognitive function, cycling time trial, methylxanthine 1 INTRODUCTION Despite advances in our understanding of the physiological responses to high altitude, there are few effective pharmacological countermeasures to offset associated symptoms of acute mountain sickness (AMS) and reductions in aerobic exercise performance upon rapid ascent. The most common and effective prophylactic treatments for

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Section: Discussioncontrasting

confidence: 99%

mentioning

confidence: 99%

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia

Subudhi

Evero

Reitinger

et al. 2020

Experimental Physiology

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“…This subsequently formed the basis of the currently accepted pathogenesis of acute mountain sickness (AMS). An additional physiological component of exerciseexacerbated hypoxemia (that is hypothesized to worsen cerebral swelling) has been incorporated into the theory (Roach and Hackett, 2001) and similarly, hypoxia during sleep may compound the situation (Kupper et al, 2008). Free radical formation, nitric oxide, and inflammatory mediators (e.g., vascular endothelial growth factor) have been proposed as mechanistic links between hypoxia and edema formation (Wilson et al, 2009).…”

Section: Introductionmentioning

confidence: 98%

The Headache of High Altitude and Microgravity—Similarities with Clinical Syndromes of Cerebral Venous Hypertension

Imray

Hargens

2011

High Altitude Medicine & Biology

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Syndromes thought to have cerebral venous hypertension as their core, such as idiopathic intracranial hypertension and jugular foramen outlet obstruction, classically result in headaches. Do they provide an insight into the cause of the headache that commonly occurs at altitude? The classic theory of the pathogenesis of high altitude headache has been that it results from increased intracranial pressure (ICP) secondary to hypoxemia in people who have less compliant intracranial volumes (Roach and Hackett, 2001). However, there does not appear to be a correlation between the headache of acute mountain sickness (AMS) and the presence of cerebral edema (Bailey et al, 2006; Wilson et al, 2009). Research has concentrated on arterial perfusion to the brain in hypoxia, but there has been little study of venous drainage. Hypoxia results in markedly increased cerebral blood flow; however, if it has been considered at all, venous outflow has to date been assumed to be of little consequence. Retinal venous distension and the increased venous blood demonstrated by near infra-red spectroscopy and more recently by MRI imply that, in hypoxia, a relative venous insufficiency may exist. Similarly, there is increasing evidence that manifestations of the fluid shift during microgravity is of similar nature to idiopathic intracranial hypertension, which is thought to be primarily a venous insufficiency condition. The unique anthropomorphic adaptations of large brained biped humans with cerebral venous systems that have to cope with large changes in hydrostatic pressure may predispose us to conditions of inflow/outflow mismatch. In addition, slight increases in central venous pressures (e.g., from hypoxia-induced pulmonary vasoconstriction) may further compromise venous outflow at altitude. A better understanding of cerebral venous physiology may enlighten us with regards the pathogenesis of headaches currently considered idiopathic. It may also enable us to trigger headaches for study and hence enable us to develop new treatment strategies.

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“…46 Headache as an isolated symptom of AMS, however, seems to be related to periodic breathing, as a prevention of the latter can reduce its incidence. 17…”

Section: Periodic Changes In Brain Perfusion and The Incidence Of Amsmentioning

confidence: 99%

“…Kupper et al were able to alleviate symptoms of AMS by administration of low-dose theophylline aiming to reduce events of periodic breathing. 17 Under physiological conditions, hypocapnia as a result of hyperventilation leads to cerebral vasoconstriction, whereas hypoventilation or apnoea may cause tissue hypoxia. We hypothesised that these physiological reactions in the face of altered breathing may cause measurable changes of the cerebral oxygen supply with possible impacts on the incidence and magnitude of the various symptoms of altitude sickness.…”

Section: Introductionmentioning

confidence: 99%

Sleeping on Mt Kilimanjaro—The Influence of Hypobaric Hypoxia on Brain Perfusion and Cerebral Tissue Oxygenation

Stein

Lampe

Pape

et al. 2014

Journal of Near Infrared Spectroscopy

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The hypobaric hypoxia encountered at high altitudes poses great challenges to the human body when adapting to these environmental conditions. Prior to full acclimatisation, a Cheyne-Stokes-like breathing pattern is commonly observed during sleep in altitude above 2500 m. We investigated the consequences of this hyperventilation and hypoventilation or apnoea on cerebral blood perfusion and tissue oxygenation during states of reduced consciousness. Perfusion and oxygen saturation of the cerebral tissue of healthy climbers were monitored with near infrared spectroscopy at night-time over the course of a six-day ascent to the summit of Mt Kilimanjaro in Tanzania.All climbers (n = 6) experienced cyclic changes in oxygenated haemoglobin and total haemoglobin with no significant alteration of the deoxygenated haemoglobin. This is the typical pattern for periodic hypocapnic arteriolar vasoconstriction with following hypoxic vasodilation in response to blood gas changes found in Cheyne-Stokes breathing. The percentage of periodic vasoactivity increased at higher altitudes and decreased on subsequent nights at the same altitude, suggesting initial maladaptation. Conversely, cycle length decreased at greater heights and increased on subsequent nights at the same level of altitude. Periodic breathing during sleep at high altitude results in periodic changes in brain perfusion without any significant drop in tissue oxygenation. Furthermore, the results of the present investigation indicate a vasomotoric component in the pathogenesis of altitude induced headache.

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Low‐Dose Theophylline Reduces Symptoms of Acute Mountain Sickness

Abstract: Low-dose, slow-release theophylline reduces symptoms of AMS in association with alleviation of events of periodic breathing and oxygen desaturations.

Cited by 31 publications

References 39 publications

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia

Combined methazolamide and theophylline improves oxygen saturation but not exercise performance or altitude illness in acute hypobaric hypoxia

The Headache of High Altitude and Microgravity—Similarities with Clinical Syndromes of Cerebral Venous Hypertension

Sleeping on Mt Kilimanjaro—The Influence of Hypobaric Hypoxia on Brain Perfusion and Cerebral Tissue Oxygenation

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